HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: a window to the infection-related headache mechanism

J Headache Pain. 2021 Aug 12;22(1):94. doi: 10.1186/s10194-021-01306-7.


Background and aim: Pathogenesis of COVID-19 -related headache is unknown, though the induction of the trigeminal neurons through inflammation is proposed. We aimed to investigate key systemic circulating inflammatory molecules and their clinical relations in COVID-19 patients with headache.

Methods: This cross-sectional study enrolled 88 COVID-19 patients, hospitalized on a regular ward during the second wave of the pandemic. Clinical characteristics of COVID-19 patients were recorded, and laboratory tests were studied.

Results: The mean ages of 48 COVID-19 patients with headache (47.71 ± 10.8) and 40 COVID-19 patients without headache (45.70 ± 12.72) were comparable. COVID-19 patients suffered from headache had significantly higher serum levels of HMGB1, NLRP3, ACE2, and IL-6 than COVID-19 patients without headache, whereas CGRP and IL-10 levels were similar in the groups. Angiotensin II level was significantly decreased in the headache group. COVID-19 patients with headache showed an increased frequency of pulmonary involvement and increased D- dimer levels. Furthermore, COVID-19 was more frequently associated with weight loss, nausea, and diarrhea in patients with headache. Serum NLRP3 levels were correlated with headache duration and hospital stay, while headache response to paracetamol was negatively correlated with HMGB1 and positively associated with IL-10 levels.

Conclusion: Stronger inflammatory response is associated with headache in hospitalized COVID-19 patients with moderate disease severity. Increased levels of the circulating inflammatory and/or nociceptive molecules like HMGB1, NLRP3, and IL-6 may play a role in the potential induction of the trigeminal system and manifestation of headache secondary to SARS-CoV-2 infection.

Keywords: ACE2; Angiotensin II; CGRP; COVID-19; HMGB1; Headache; IL-10; IL-6; Inflammation; NLRP3.

MeSH terms

  • COVID-19*
  • Cross-Sectional Studies
  • HMGB1 Protein*
  • Headache
  • Humans
  • Interleukin-6
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Peptidyl-Dipeptidase A
  • SARS-CoV-2


  • HMGB1 Protein
  • Interleukin-6
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Peptidyl-Dipeptidase A